Intellectual disability (ID) is the most common developmental disorder in the US. Patients with ID suffer from significantly subaverage intellectual function (IQ d70), which impinges on quality of life. In a collaborative effort, our laboratory has recently discovered novel mutations causative for autosomal recessive ID (ARID). These mutations are found in ZC3H14, a zinc finger polyadenosine RNA binding protein. This finding uncovers the molecular basis for disease in these patients and provides strong evidence that ZC3H14 is essential for proper brain function. Functional characterization of ZC3H14 is crucial for understanding both normal brain function and the molecular mechanism underlying ARID in these patients. Studies of ZC3H14 orthologs in model organisms provide insight into the role of this protein in post-transcriptional regulation of gene expression and key evidence for a critical role in neurons. We plan to exploit mouse neuronal cell lines to address our hypothesis that ZC3H14 is required for proper expression of specific mRNA targets that are critical for neuronal function. For our first aim, we will validate candidate ZC3H14 targets and use a discovery-based approach to search for novel targets of ZC3H14. In our second aim, we will both examine poly(A) tail length of specific transcripts and use state-of-the-art microscopy to determine whether ZC3H14 is required for proper localization of target mRNAs. By understanding how ZC3H14 controls expression of important target mRNAs, we can begin to address molecular mechanisms critical for normal brain function. Our long-term goal is to understand how dysregulation of post-transcriptional control of mRNA in neurons leads to neuronal dysfunction and consequently impaired brain function. PUBLIC HEALTH RELEVANCE: The goal of this study is to understand how proteins called RNA binding proteins regulate the way in which information is transferred from the genetic code within the cell nucleus to the translation machinery in the cell cytoplasm. Our study focuses on one such protein that is mutated in patients with brain dysfunction called intellectual disability. We hope our studies will allow us to understand the important functions of this class of proteins and thus lay the groundwork for developing improved therapies for patients with defects in this information transfer process.